Use of 4-(isoxazolyl)-thiazole-2-oxamic acid derivatives

ABSTRACT

Use of 4-(isoxazolyl)-thiazole-2-oxamic acid derivatives; method for preparing them and intermediate compounds useful for their preparation. 
     Said compounds possess antiarthritic activity; compositions for pharmaceutical use containing said compounds as the active ingredients are also described.

This invention relates to the use of 4-(isoxazolyl)-thiazol-2-oxamicacid derivatives as antiarthritic agents, their preparation,pharmaceutical composition containing them, and new4-(isoxazolyl)-thiazole compounds.

More particularly, this invention relates to the use of the compounds offormula: ##STR1## wherein

R and R₁ which may be the same or different represent a hydroxy group; ahydrogen or halogen atom; a C₁ -C₆ alkyl or alkoxy group optionallysubstituted by from one to three substituents selected from the groupconsisting of halogen, hydroxy, alkoxy, amino, carboxy, alkoxycarbonyl,alkoxalyloxy and phenyl, the latter in turn optionally substituted byfrom one to three substituents selected from the group consisting ofhalogen, hydroxy, alkoxy, amino and trifluoroalkyl; a phenyl groupoptionally substituted by from one to three substituents selected fromthe group consisting of halogen, hydroxy, alkoxy, amino andtrifluoromethyl;

R₂ is a hydroxy group, an OR₃ group or an NR₄ R₅ group;

R₃ is a C₁ -C₆ alkyl group optionally substituted with from one to threesubstituents selected from the group consisting of hydroxy, alkoxy,amino, carboxy and alkoxycarbonyl; a C₅₋₆ cycloalkyl group optionallysubstituted by from one to three alkyl groups; a C₇ -C₉ phenylalkylgroup optionally substituted on the phenyl ring by from one to threesubstituents selected from the group consisting of halogen, methyl andmethoxy group; a group of the formula --(CH₂ --CH₂ --O)_(n) --R₆ whereinn is an integer number from 2 to 4 and R₆ is a hydrogen atom or an alkylgroup; R₄ and R₅ which may be the same or different are a hydrogen atom,an alkyl, a C₅ -C₆ cycloalkyl, a C₇ -C₉ phenylalkyl, or a phenyl group;or R₄ and R₅ together with the nitrogen atom to which they are linked,form a 1-piperidyl, 1-piperazinyl, 4-methyl-1-piperazinyl, pirazolyl,thiazolyl or imidazolyl radical; or either R₄ or R₅ is a hydrogen atomand the other a group of the formula ##STR2## wherein

R and R₁ have the above indicated meanings.

R₇ is a hydrogen atom or a C₁ -C₃ alkyl radical.

Another object of this invention is the use of the salts of thecompounds of formula I in which R₂ is a hydroxy group withpharmaceutically acceptable organic and inorganic bases and the salts ofthe compounds of formula I in which R₂ contains a basic function withpharmaceutically acceptable organic and inorganic acids.

If not otherwise specified

alkyl means a straight or branched C₁ -C₄ alkyl group;

alkoxy means a C₁ -C₄ alkoxy group;

alkoxycarbonyl means an alkoxycarbonyl group having from 1 to 4 carbonatoms in the alkoxy moiety;

halogen means fluorine, chlorine, bromine or iodine atom.

Depending on the meaning of the substituents, some of the compounds offormula I can exist in the form of isomers.

It is an object of this present invention either the use of the isomermixtures or of the single isomers obtained by separation from themixture or by stereospecific synthesis.

Examples of compounds included in formula I are the following

    X--NH--CO--CO--OH

    X--NH--CO--CO--O.sup.- Na.sup.+

    X--NH--CO--CO--O.sup.-. H.sub.3.sup.+ N--CH.sub.2 --CH.sub.2 --OH

    X--NH--CO--CO--O.sup.- H.sub.3.sup.+ N--C(CH.sub.2 OH).sub.3

    X--NH--CO--CO--O--C.sub.2 H.sub.5

    X--NH--CO--CO--O--CH.sub.2 --CH.sub.2 --OCH.sub.3

    X--NH--CO--CO--O--CH.sub.2 --CH.sub.2 --O--C.sub.2 H.sub.5

    X--NH--CO--CO--NH.sub.2

    X--NH--CO--CO--NH--CH(CH.sub.3).sub.2 ##STR3## wherein X is the group ##STR4## wherein R, R.sub.1 and R.sub.7 have the same meaning as set forth above.

Typical examples of R and R₁ include fluorine, chlorine, bromine,iodine, propoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, methyl, ethyl,propyl, isopropyl, hydroxypropyl, hydroxyethyl, hydroxymethyl,propyloxypropyl, propyloxymethyl, methyloxyethyl, metoxymethyl,ethoxymethyl, ethoxalyloxypropyl (--C₃ H₆ OCOCOOC₂ H₅),propoxalyloxymethyl (--CH₂ OCOCOOC₃ H₇), ethoxalyloxymethyl (--CH₂OCOCOOC₂ H₅), 2-bromophenyl, 2-iodophenyl, 2-chlorophenyl,2,6-dichlorophenyl, 2-chloro-6-fluorophenyl, methoxy, ethoxy, propoxy,phenylethoxy and benzyloxy.

Preferred meanings of R and R₁ are hydrogen, chlorine, bromine, hydroxy,methyl, methoxy, ethoxy, benzyloxy, phenyl, halosubstituted phenylhydroxymethyl, methoxymethyl, ethoxalyloxymethyl and carbethoxy.

The compounds of formula (I) are valuable immunodepressive agents inmammals.

A further object of this invention are the compounds of formula (I)except when R₂ is hydroxy or OR₃ and the isoxazolyl radical is a 3- or a5-isoxazolyl radical.

Preparation of the compounds of formula I is performed according toprocedures known in organic chemistry and is accomplished through thereactions set forth in scheme 1 below ##STR5## (R, R₁, R₂, R₃, R₄, R₅and R₇ have the meanings set forth in connection with general formula I;Y is chlorine or bromine; W is chlorine, bromine or R₃ O)

The bromoacetyl-isoxazole derivative (formula II) is condensed (reaction1, scheme 1) with thiourea to give a derivative of2-amino-4-isoxazolyl-thiazole (formula III).

Condensation is performed by heating the mixture of reactants in aprotic or aprotic polar solvent at a temperature preferably between 50°C. and 100° C.

The compond of formula III is then reacted (reaction 2) with a halide ofoxalic acid monoester obtaining the compounds of formula I wherein R₂ isan OR₃ group.

Reaction 2 is performed preferably in pyridine or in an inert solvent inthe presence of an acid-acceptor.

From the compounds of formula I wherein R₂ =OR₃ are prepared by reactionwith an aqueous inorganic base (reaction 3) the free acids (I, R₂ =OH)and with an organic base of formula HNR₄ R₅ (reaction 4) the compoundsof formula I wherein R₂ =NR₄ R₅.

As appears evident to persons skilled in the art, the compounds of thisinvention may be prepared by alternative procedures with respect tothose set forth in scheme 1.

For example, the esters of formula I (R₂ =OR₃) may also be prepared bytransesterification or other esters of formula I, or by reacting an acylhalide of an acid of formula I (R₂ =OH) with the suitable alcohol offormula R₃ -OH.

Similarly, the compounds of formula ##STR6## are normally preparedaccording to the reactions of scheme 1 but, in the case where the twopairs of substituents R and R₁ are identical, they can also be preparedby condensing 2 moles of the suitable compound of formula III withoxalyl dihalide (W--CO--CO--Y; W=Y=halide)

Compounds of formula I in the form of salts are prepared by reacting acompound of formula I wherein R₂ =OH with a pharmaceutically acceptableorganic or inorganic base.

Similarly, the salts may be also prepared by reacting a compound offormula I wherein R₂ contains a basic function (e.g. R₂=4-methyl-1-piperidinyl) with a pharmaceutically acceptable organic orinorganic acid.

The compounds of formula II are in part compounds known as such or atthe precursor level.

In any case, they are prepared by known techniques.

An example of synthesis is given in scheme 2. ##STR7##

Reaction 1 of Scheme 2 is performed by reacting an acyl chloride IV withdiethylmalonate or a diethylalkylmalonate and carbon tetrachloride inthe presenc of magnesium, according to known techniques.

Reaction 2 of scheme 2 is performed by brominating an intermediate Vwith pyridine perbromide hydrobromide or other brominating agents insolvents such as carbon tetrachloride, chloroform, methyl chloride, etc.

Among the known compounds of formulas V and II may be mentioned

3-bromo-5-acetyl-isoxazole (European Pat. No. 16,255),

3-methoxy-5-acetyl-isoxazole (Acta Chem. Scan., B, 28, 639, 1974),

3-bromo-5-bromoacetyl-isoxazole (European Pat. No. 16,255),

4-acetyl-3-phenyl-5-methylisoxazole (Gazz. Chim. It., 76, 200, 1946),

4-acetyl-3-(2-chlorophenyl)-5-methylisoxazole (Nippon Kagaku Z., 92,639, 1971),

3-bromoacetyl-5-phenyl-isoxazole (J. Med. Chem., 10, 411, 1967)

The compounds of formula III are new when the isoxazolyl group is a4-isoxazolyl radical and are a further object of this invention.

The pharmacological investigation proved that the compounds of thisinvention possess interesting antiarthritic properties.

Antiarthritic activity was appraised using the test for Freundexperimental arthritis induced in the rat by a subplantar injection of a0.5% solution of killed Butyricum mycobacteria in parrafin oil asdescribed by Newbould B. B. (Brit. J. Pharmacol., 1963, 21, 127).

Compounds found to be active in Freund's experimental arthritis wereshown to have considerable clinical usefulness in the treatment ofrheumatoid arthritis.

The therapy of rheumatoid arthritis, a disease of the connective tissueswith unclear aetiology, provides for the employment mainly of drugsbelonging to two classes: nonsteroid and immunodepressive antiphlogisticagents.

The experimental model of Freund's arthritis used for thepharmacological investigation of the compounds of this invention makesit possible not only to appraise pharmacological activity but to acquiresound indications on the mechanism of the action of the testedcompounds.

In this experimental model the drugs with antiinflammatory activity aremore effective in the stage sustained predominantly by a specificinflammatory mechanism (primary stage), while the drugs withimmunodepressive activity are more effective in the stage sustainedprincipally by an immunity mechanism (secondary stage).

The pharmacological investigation of the compounds of this invention wasconducted by administering to the experimental animal dosage levels offrom 20 to 40 mg/kg/day for a period of 28 consecutive days beginningthe day before innoculation of the mycobacteria.

Pharmacological activity was measured by determining both the velocityof erythrosedimentation (VES) and change in volume of the hind limbs.

The limb which was the seat of the innoculation represents the primarystage while the contra-lateral limb, where the onset of the pathologicalprocess takes place about the 12th day after innoculation, representsthe secondary stage.

Treatment of the mycobacteria-innoculated animals withN-[4-(3-bromo-5-isoxazolyl)-2-thiazolyl]-oxamide brought the VES indexalmost to normalization in 40% of the animals when 40 mg/kg wereadministered orally and in 70% of the animals when 20 mg/kg wereinjected peritoneally.

The peritoneal treatment also led to a 60% inhibition of volume growthin the contra-lateral limb (secondary stage).

Treatment of the animals withN,N'-bis-[4-(3-bromo-5-isoxazolyl)-2-thiazolyl]-oxamide (35 mg/kgperitoneally) led to maintenance of the VES around the values exhibitedby the group of animals not innoculated with mycobacteria, i.e. 100%protection.

As regards the increase in volume of the contra-lateral limb, peritonealadministration of 35 mg/kg ofN,N'-bis-[4-(3-bromo-5-isoxazolyl)-2-thiazolyl]-oxamide gave 70%increase protection.

The compounds investigated did not show any significant effect on theinflammatory development stage of experimental arthritis.

Systemic tolerability of the compounds proved very favourable. From thetests conducted in the experimental animal no toxic phenomena appearedwith 0.5 g/kg doses in parenteral administration and 1.5 g/kg with oraltreatment. The ratio of the effective pharmacological dose to thetolerated dose proved very favourable.

The therapeutical indications of the compounds in question arerepresented by the different syndromes which accompany the arthritic andrheumatic processes.

The therapeutic dosage ranges from 5 to 500 mg/day.

The compounds of this invention are useful for treating the varioussyndromes which accompany the arthritic and rheumatic processes.

Another object of the present invention are the pharmaceuticalcompositions containing as active ingredient the compounds of formula(I) or their pharmaceutically acceptable salts.

These compositions can contain the active ingredient together withpharmaceutically acceptable organic or inorganic solid or liquidexcipients and can be suitable for topical, oral, parenteral, or rectaladministration.

The finished pharmaceutical preparations can be solid, such as forexample tablets, pills, capsules, powders, granules, suppositories; orliquid such as for example solutions, suspensions, emulsions, orsemiliquids such as creams and ointments. They can even be prepared insuch a manner that the release of the drug is prolonged afteradministration.

In addition to the excipients they can contain preservative,stabilizing, wetting and emulsifying agents, salts to regulate osmoticpressure, buffers, colourings, flavourings, etc.

They can be prepared according to known methods and can also containother therapeutic ingredients.

In order to better illustrate the present invention the followingexamples are now given.

EXAMPLE A 1-[3-(2-chloro-6-fluorophenyl)-5-isoxazolyl]-ethanol

27.60 g (273 mmol) of triethylamine were added dropwise to a solution of28.4 g (136.5 mmol) of alpha, 2-dichloro-6-fluorobenzaldoxime and 19.14g (273 mmol) of 3-butin-2-ole in 250 ml of benzene kept under stirringat 8°-10° C.

When the addition was over the mixture was heated to 60° C.; after 1hour the mixture was cooled and extracted with 10% hydrochloric acid andthen with water.

Evaporation of the organic phase gave 31.1 g of an oil which waspurified by distillation and the fraction boiling at 140°-150° C. (0.3mmHg) was collected. 1HNMR (CDCl₃): delta 7.6-7 (m, 3H); 6.4 (s, 1H);5.1 (q, 1H); 1.6 (t, 3H).

EXAMPLE B (1) 3-(2-chloro-6-fluorophenyl)-5-acetylisoxazole

To a solution of 30 g (124 mmol) of1-[3-(2-chloro-6-fluorophenyl)-5-isoxazolyl]-ethanol in 187 ml of aceticacid maintained under stirring at 5° C. were added dropwise 9.07 g (90.7mmol) of CrO₃ in 9.34 g of water and 132 ml of acetic acid.

The mixture was kept overnight under stirring at room temperature; thesolvent was then removed by evaporation and the residue was taken upwith water, made neutral with sodium bicarbonate and extracted withethyl ether.

The ethereal extracts were combined and washed with water, dried andevaporated to dryness; 27.8 g of an orange oily product were obtained.The oil was distilled under reduced pressure and the fraction boiling at120°-122° C. (0.4 mmHg) was collected; yield, 23.7 g.

The oil was allowed to crystallize by standing and then recrystallizedfrom isopropyl ether; m.p. 46°-47° C. 1HNMR (DMSO): delta 7.9-7.3 (m,4H); 2.8 (s, 3H).

In a similar manner were obtained:

3-carbethoxy-5-acetylisoxazole, Yield, 82%; m.p. 67°-68° C. (isopropylether); 1HNMR (CDCl₃): delta 7.3 (s, 1H); 4.5 (q, 2H); 2.7 (s, 3H); 1.5(t, 3H).

The starting compound, i.e. 1-(3-carbethoxy-5-isoxazolyl)-ethanol, wasprepared according to European Pat. No. 28,355.

3-methoxymethyl-5-acetylisoxazole, Yield, 58.5%; colourless oil, b.p.72°-74° C. (0.4 mmHg); 1HNMR (CDCl₃): delta 7.0 (s, 1H); 4.6 (s, 2H);3.4 (s, 3H); 2.6 (s, 3H).

The starting compound, i.e. 1-(3-methoxymethyl-5-isoxazolyl)-ethanol,was prepared according to German Pat. No. 2,754,832.

(2) 3-benzyloxy-5-acetylisoxazole

2.2 g (90.5 mmol) of magnesium turnings were added under stirring to asolution of 14 g (87 mmol) of diethyl malonate in 78 ml of ethyl ethercontaining 63 g of anhydrous ethyl alcohol and 0.90 ml of carboniumtetrachloride.

The mixture was refluxed for 2 hours and then was added dropwise asolution of 18.8 g (79 mmol) of 3-benzyloxy-5-isoxazolylcarbonylchloride (Belgian Pat. No. 665,249) in 65 ml of ethyl ether.

The mixture was refluxed for 2 hours, cooled to room temperature and 159ml of 2M sulfuric acid were added.

After vigorous stirring, the organic layer was separated, washed withwater and evaporated to dryness.

The thus obtained oily residue (29.9 g) was added to a solution of 4.8 gof concentrate sulfuric acid in 36.3 ml of acetic acid and 25 ml ofwater; the mixture was refluxed for 8 hours.

The mixture was cooled to 20° C. and made neutral (pH 6.5) with 10Mpotassium hydroxide at constant temperature.

The mixture was extracted with chloroform; the combined organic extractswere evaporated to give an oily residue which was taken up with 150 mlof hexane. The crystalline precipitate was collected by filtration (6.7g; Yield, 39%) and recrystallized from isopropyl ether. m.p. 77°-78° C.1HNMR (CDCl₃): delta 7.5 (m, 5H); 7.2 (s, 1H); 5.4 (s, 2H); 2.5 (s, 3H).

(3) 3-(2-chloro-6-fluorophenyl)-5-methyl-4-acetylisoxazole

To a solution of 2.3 g (100 mmol) of sodium in 220 ml of anhydrousethanol were added 10 g (100 mmol) of acetyl acetone.

The reaction mixture was cooled to 0° C. and 17 g (81.6 mmol) of alpha,2-chloro-6-fluorobenzaloxime (German Patent Application No. 2,323,809)were added dropwise while stirring vigorously and maintaining thetemperature at about 5° C.

The mixture was stirred overnight at room temperature and then madeneutral with 10% hydrochloric acid. The mixture was concentrated todryness and the residue was taken up with 100 ml of water and 150 ml ofethyl ether.

The organic layer was separated, washed with dilute sodium hydroxide andthen with water till neutral.

The solvent was removed by evaporation and the oily residue distilledunder reduced pressure; p.b. 129°-131° C. (0.5 mmHg); Yield, 14.5 g(70%) of a clear colourless oil. 1HNMR (CDCl₃): delta 7.9-7.3 (m, 3H),2.8 (s, 3H), 2.3 (s, 3H).

EXAMPLE C (1) 3-chloro-5-bromoacetylisoxazole

28.65 g (179 mmol) of bromine in 20 ml of chloroform were added dropwisein 10 minutes to a solution of 25 g (172 mmol) of3-chloro-5-acetylisoxazole containing 4.9 ml of glacial acetic acidwhile the reaction mixture was maintained under stirring at 48°-50° C.

After 5 minutes the mixture was poured into 300 g of water and crushedice.

The organic layer was separated, washed with water, dried and evaporatedto residual.

Yield, 37 g (96%) of an oily compound which can be purified bydistillation; b.p. 97°-99° C. (2 mmHg). 1HNMR (CDCl₃): delta 7.00 (s,1H), 4.37 (s, 2H).

In a similar manner were prepared the following compounds:

3-methoxy-5-bromoacetylisoxazole, (from 3-methoxy-5-acetyl-isoxazole,Acta Chem. Scand. 28 B, 639, 1947); Yield, 91%; deliquescent crystallinecompound; 1HNMR (CDCl₃): delta 6.63 (s 1H); 4.33 (s, 2H); 4.00 (s, 3H).

3-benxyloxy-5-bromoacetylisoxazole, Yield, 83%; white crystallinecompound, m.p. 80°-81° C. (isopropyl ether); 1HNMR (DMSO-d₆): delta 7.37(s, 5H), 7,29 (s, 1H), 5.28 (s, 2H), 4.71 (s, 2H).

3-phenyl-5-methyl-4-bromoacetylisoxazole, (from3-phenyl-5-methyl-4-acetylisoxazole, Gazz. Chim. It. 76, 200, 1946);Yield, 87%; white crystalline compound, m.p. 46°-48° C. (isopropylether); 1HNMR (CDCl₃): delta 7.57 (m, 5H), 3,22 (s, 2H), 2.71 (s, 3H).

5-hydroxymethyl-3-bromoacetylisoxazole, (from5-hydroxylethyl-3-acetylisoxazole, II Farmaco, Ed. sci, 39, 487, 1984);Yield 94%; oily compound, b.p. 160° C./0.3 mmHg, 1HNMR (CDCl₃): delta6.72 (s, 1H), 4.85 (s, 2H), 4.60 (s, 2H).

3-methyl-5-bromoacetylisoxazole, (from 3-methyl-5-acetylisoxazole, Gass.Chim. Ital. 72, 242, 1942); Yield, 87%; white crystalline compound, m.p.44°-46° C. (isopropyl ether); 1HNMR (CDCl₃): delta 7.00 (s, 1H), 4.42(s, 2H), 2.43 (s, 3H).

3-(2-chloro-6-fluorophenyl)-5-bromoacetylisoxazole, Yield, 85%; oilycompound, b.p. 145°-150° C./0.3 mmHg; 1HNMR (CDCl₃): delta 7.8-7 (m,4H), 4.60 (s, 2H).

3-carbethoxy-5-bromoacetylisoxazole, Yield, 83%; white crystallinecompound, m.p. 74°-75° C. (isopropyl ether); 1HNMR (CDCl₃): delta 7.5(s, 1H), 4.52 (q, 2H), 4.50 (s, 2H), 1.5 (t, 3H).

3-methoxymethyl-5-bromoacetylisoxazole, (from3-methoxy-5-acetylisoxazole, Acta Chem. Scand. 28 B, 639, 1947); yield,91%; oily compound. 1HNMR (CDCl₃): delta 7.1 (s, 1H), 4.4 (s, 2H), 3.4(s, 3H).

1-(3-bromo-5-isossalolyl)-2-bromo-1-butanone, Yield, 98%; whitecrystalline compound, m.p. 53°-54° C. (hexane). 1HNMR (CDCl₃): delta 7.2(s, 1H), 5.0 (t, 1H), 2.2 (m, 4H), 1.1 (t, 3H).

3-(2-chloro-6-fluorophenyl)-5-methyl-4-bromoacetylisoxazole, Yield, 86%;white crystalline compound, m.p. 74°-75° C. (isopropyl ether). 1HNMR(CDCl₃): delta 7.88-7.10 (m, 3H), 3.80 (s, 2H) 2.84 (s, 3H).

EXAMPLE D (1) 2-amino-4-(3-bromo-5-isoxazolyl)-thiazole

A mixture of 32.4 g (120.4 mmol) of 5-bromoacetyl-3-bromoisoxazole and18.4 g (240 mmol) of thiourea in 400 ml of anhydrous ethanol wasrefluxed for 90 minutes.

The solvent was removed by distillation and the residue was taken upwhile stirring with 750 ml of ethyl ether and 160 ml of 10% aqueouspotassium hydroxide. The ethereal extract was separated and washed with50 ml of ethyl ether.

The extracts and the ethereal washings were combined and washed withwater till neutral, dried over sodium sulfate and then evaporated todryness.

The crystalline residue (28.7 g; 97%) was purified by recrystallizationfrom methanol, m.p. 160°-162° C.; 1HNMR (DMSO-d₆): delta 7.47 (s, 1H);6.97 (s, 1H).

In a similar manner were prepared the following compounds:

2-amino-4-[3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolyl]-thiazole,Yield, 81.5%; crystalline compound, m.p. 148°-149° C.(isopropylalcohol); 1HNMR (DMSO-D₆): delta 7.9-7.4 (m, 3H), 6.0 (s, 1H),2.8 (s, 3H).

2-amino-4-(3-phenyl-5-methyl-4-isoxazolyl)-thiazole, Yield, 69.5%;crystalline compound, m.p. 223°-224° C. (methyl alcohol); 1HNMR(DMSO-d₆): delta 7.62 (s, 1H), 6.43 (s, 1H), 2.58 (s, 3H).

(2) 2-amino-4-(3-methoxy-5-isoxazolyl)-thiazole

A mixture of 9.2 g (41.8 mmol) of 3-methoxy-5-bromoacetylisoxazole and6.36 g (83.6 mmol) of thiourea in 140 ml of methyl alcohol was refluxedfor 90 minutes and then cooled for 1 hour with an ice bath.

The precipitate was collected by filtration and added to 120 ml of an 1%solution of sodium hydroxide while stirring vigorously.

The solution was allowed to stand for 30 minutes at room temperature,the precipiate was collected by filtration and washed with water tillneutral.

Yield, 6.9 g (83.7%); after recrystallization from methyl alcohol thecompound melts at 215°-217° C. 1HNMR (DMSO-d₆): delta 7.37 (s, 1H), 6.43(s, 1H), 4.03 (s, 3H).

In a similar manner was prepared the

1-amino-4-(5-hydroxylmethyl-3-isoxazolyl)-thiazole, Yield, 62.5%; m.p.185°-187° C. (methyl alcohol); 1HNMR (DMSO-d₆): delta 7.3 (s, 1H), 6.7(s, 1H), 5.7 (t, 1H) 4.6 (d, 2H).

(3) 2-amino-4-(3-chloro-5-isoxazolyl)-thiazole

A mixture of 11.2 g (50 mmol) of 3-chloro-5-bromoacetylisoxazole and 7.6g (100 mmol) of thiourea in 164 ml of ethyl alcohol was refluxed for 90minutes and then cooled for 1 hour with an ice bath.

The precipiate was collected by filtration and added to a mixture of 25ml of a 10% aqueous solution of sodium hydroxide and 100 ml of ethylacetate under vigorous stirring.

The organic layer was separated, washed, dried and evaporated todryness. Yield, 7.7 g (77%); after recrystallization from acetonitrilethe compound melts at 169°-170° C. 1HNMR (DMSO-d₆): delta 7.4 (s, 1H),6.9 (s, 1H).

In a similar manner the following compounds were prepared:

2-amino-4-(3-benzyloxy-5-isoxazolyl)-thiazole, Yield, 76.5%; m.p.129°-131° C. (acetonitrile); 1HNMR (CDCl₃): delta 7.3 (s, 1H), 6.5 (s,1H), 5.4 (s, 2H).

2-amino-4-(5-phenyl-3-isoxazolyl)-thiazole, (from5-phenyl-3-bromoacetylisoxazole, J. Med. Chem. 10, 411, 1967). Yield,74.5%; m.p. 215°-216° C. (methyl alcohol). Anal: S=12.98% (Calcd.13.18%)

2-amino-4-(3-phenyl-5-isoxazolyl)-thiazole, (from3-phenyl-5-bromoacetylisoxazole, J. Med. Chem. 10, 411, 1967). Yield,65.5%; m.p. 192°-193° C. (acetonitrile). Anal.: S=13.39% (Calcd. 13.18%)

2-amino-4-[3-(2-chloro-6-fluorophenyl)-5-isoxazolyl]-thiazole, Yield,56.6%; m.p. 168°-169° C. (acetonitrile); Anal: S=11.03% (Calcd. 10.84%).

2-amino-4-(3-methyl-5-isoxazolyl)-thiazole, Yield, 57%; m.p. 208°-210°C. (acetonitrile); 1HNMR (DMSO-d₆): delta 7.03 (s, 1H), 6.5 (s, 1H), 2.3(s, 3H).

2-amino-4-(3-methoxymethyl-5-isoxazolyl)-thiazole, Yield, 49%; m.p.137°-138° C. (acetonitrile); 1HNMR (DMSO-d₆): delta 7.3 (s, 1H), 6.6 (s,1H), 4.5 (s, 2H), 3.4 (s, 3H).

2-amino-4-(3-bromo-5-isoxazolyl)-5-ethylthiazole, Yield, 70%; m.p.151°-152° C. (acetonitrile);

1HNMR (DMSO-d₆): delta 6.8 (s, 1H), 3.0 (q, 2H), 1.2 (t, 3H).

(4) 2-amino-4-(3-hydroxymethyl-5-isoxazolyl)-thiazole

4.4 g (116.2 mmol) of sodium boron hydride were added portionwise to asolution of 13.9 g (58.1 mmol) of2-amino-4-(3-carbethoxy-5-isoxazolyl)-thiazole in 40 ml of dimethylformamide and 80 ml of methyl alcohol under stirring at about 35° C.

When the addition was over, the reaction mixture was stirred at roomtemperature for 90 minutes and then was made acid by adding carefully 60ml of 10% hydrochloric acid.

The reaction mixture was evaporated under reduced pressure, the residuewas taken up with water and made alkaline with potassium carbonate.

The precipiate was collected by filtration and washed with water. Yield,11.1 g (97%); m.p. 184°-185° C. (acetonitrile). 1HNMR (DMSO-d₆): delta7.4 (s, 1H), 6.6 (s, 1H), 4.6 (d, 2H).

(5) 2-amino-4-(3-carbethoxy-5-isoxazolyl)-thiazole

A solution of 54.8 g (209 mmol) of 3-carbethoxy-5-bromoacetylisoxazoleand 31.8 g (418 mmol) of thiourea in 685 ml of ethanol was refluxed for90 minutes and then cooled for 1 hour with an ice bath.

The precipitate was collected by filtration and added to an aqueoussolution of potassium bicarbonate under vigorous stirring.

The reaction mixture was shaken with ethyl acetate. The combined organicextracts were washed with water, dried and evaporated. Yield, 43.4 g(86.7%); m.p. 156°-157° C. (acetonitrile). 1HNMR (DMSO-d₆): delta 7.4(s, 1H), 7.0 (s, 1H), 4.4 (d, 2H), 1.4 (t, 3H).

(6) 2-amino-4-(3-hydroxy-5-isoxazolyl)-thiazole hydrobromide

A mixture of 13.5 g (68.5 mmol) of2-amino-4-(3-methoxy-5-isoxazolyl)-2-thiazol and 135 ml of 48%hydrobromic acid was heated while stirring with an outer bath at 100° C.for one hour.

After cooling with a water/ice bath the precipitate was collected byfiltration under reduced pressure and dried.

13.3 g (73.6%) of a white crystalline compound were obtained which werepurified by crystallization from 1% hydrobromic acid. 1HNMR (DMSO-d₆):delta 7.5 (s, 1H); 6.6 (s, 1H).

EXAMPLE E (1) Ethyl 4-(3-bromo-5-isoxazolyl)-thiazole-2-oxamate

To a mixture of 7.38 g (30 mmol) of4-(3-bromo-5-isoxazolyl-2-thiazolamine and 3.50 g (34.6 mmol) oftriethylamine in 60 ml of pyridine, stirred at a temperature not above10° C. were added dropwise 4.71 g (34.5 mmol) of ethoxalyl chloride.

At the end of the addition the solution was stirred overnight and thendiluted with 120 ml of water.

The precipitate was collected by filtration and washed on the filterwith abundant water.

After vacuum drying at 50° C. the compound was recrystallized two timesfrom 110 ml and 130 ml of acetonitrile respectively to give 6.90 g of acrystalline compound analitically pure; m.p. 196.5°-197° C. 1HNMR(DMSO)-d₆): delta 8.20 (s, 1H); 7.20 (s, 1H); 4.42 (q, 2H,); 1.40 (t,3H).

In a similar manner was prepared the following compound:

Ethyl-4-(3-phenyl-5-methyl-4-isoxazolyl)-thiazole-2-oxamate, Yield, 78%;m.p. 157°-159° C. (acetonitrile); 1HNMR (DMSO-d₆): delta 7.6 (m, 5H),7.3 (s, 1H), 3.2 (q, 2H), 2.6 (s, 3H), 1.3 (s, 3H).

(2) Ethyl 4-(3-methoxy-5-isoxazolyl)-thiazole-2-oxamate

To a mixture of 6.60 g (33.5 mmol) of2-amino-4-(3-metoxy-5-isoxazolyl)-thiazole in 67 ml of pyridine whilestirring at 5°-10° C. were added dropwise 5.25 g (38.5 mmol) ofethoxalyl chloride.

The reaction mixture was maintained under stirring overnight, thenpoured into 120 g of crushed ice and made acid with concentratehydrochloric acid.

The mixture was extracted wih 750 ml of 1,2-dichloroethane, the organiclayer was separated and washed with water.

The organic extracts were evaporated; Yield, 9.40 g (94.5%); m.p.204°-205° C.; 1HNMR (DMSO-d₆): delta 8.10 (s, 1H), 6.6 (s, 1H), 4.4 (q,2H), 4.0 (s, 3H), 1.4 (t, 3H).

In a similar manner were prepared the following compounds:

Ethyl 4-(5-phenyl-3-isoxazoly)-thiazole-2-oxamate, Yield, 47%; m.p.169°-170° C. (ethyl alcohol); 1HNMR (DMSO-d₆): delta 8.2-7.4 (m, 5H),8.1 (s, 1H), 7.5 (s, 1H), 4.4 (q, 2H), 1.4 (t, 3H).

Ethyl 4-(3-ethoxalyloxymethyl-5-isoxazolyl)-thiazole-2-oxamate, Yield,68%; m.p. 150°-151° C. (ethyl alcohol); 1HNMR (DMSO-d₆): delta 8.1 (s,1H), 7.0 (s, 1H), 5.5 (s, 2H), 4.4 (q, 4H), 1.4 (t, 6H).

Benzyl 4-[3-(2-chloro-6-fluorophenyl-5-isoxazolyl]-thiazole-2-oxamate,Yield, 67% m.p. 199°-200° C. (acetonitrile); 1HNMR (DMSO-d₆): delta 8.3(s, 1H), 7.5 (m, 8H), 7.2 (s, 1H), 5.5 (s, 2H).

Cyclohexyl4-[3-(2-chloro-6-fluorophenyl-5-isoxazolyl]-thiazole-2-oxamate, Yield,74%; m.p. 77°-78° C. (ethyl alcohol); 1HNMR (DMSO-d₆): delta 8.2 (s,1H), 7.6 (m, 3H), 7.1 (s, 1H), 4.9 (m, 1H), 2.2-1.1 (m, 10H).

(3) 2-ethoxyethyl 4-(3-benzyloxy-5-isoxazolyl)-thiazole-2-oxamate.

To a mixture of 5.6 g (20.5 mmol) of2-amino-4-(3-benzyloxy-5-isoxazolyl)-thiazole in 37.4 ml of pyridinemaintained under stirring at 5° C. were added dropwise 4.25 g (23.6mmol) of 2-ethoxyethyloxalyl chloride.

The reaction mixture was maintained under stirring overnight, thenpoured into 100 g of crushed ice, made acid with concentratehydrochloric acid and extracted with chloroform.

The chloroform extracts were washed with water, dried and evaporated todryness. The residue (8.30 g) was recrystallized from 65 ml ofacetonitrile; m.p. 142°-144° C. 1HNMR (DMSO-d₆): delta 8.2 (s, 1H), 7.6(m, 5H), 6.7 (s, 1H), 4.5 (m, 2H), 3.8 (m, 2H), 3.6 (q, 2H), 1.2 (t,3H).

In a similar manner were obtained the following compounds:

2-ethoxyethyl 4-(5-phenyl-3-isoxazolyl)-thiazole-2-oxamate, Yield, 82%;m.p. 146°-147° C. (acetonitrile); 1HNMR (DMSO-d₆): delta 8.1 (s, 1H),8.1-7.5 (m, 5H), 7.5 (s, 1H), 4.5 (m, 2H), 3 (m, 2H), 3.6 (q, 2H), 1.2(t, 3H).

2-ethoxyethyl 4-(3-phenyl-5-isoxazolyl)-thiazole-2-oxamate, Yield, 84%;m.p. 146°-147° C. (acetonitrile); 1HNMR (DMSO-d₆): delta 8.2 (s, 1H),8.2-7.4 (m, 5H), 7.4 (s, 1H), 4.5 (m, 2H), 3.8 (m, 2H), 3.6 (q, 2H), 1.2(t, 3H).

2-ethoxyethyl4-[3-(2-chloro-6-fluorophenyl)-5-isoxazolyl]-thiazole-2-oxamate. Yield,87%; m.p. 140°-141° C. (acetonitrile); 1HNMR (DMSO-d₆): delta 8.2 (s,1H), 7.7 (m, 3H), 7.2 (s, 1H), 4.5 (m, 2H), 3.8 (m, 2H), 3.6 (q, 2H),1.2 (t, 3H).

2-ethoxyethyl4-[3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolyl]-thiazole-2-oxamate,Yield, 85%; m.p. 47°-58° C. 1HNMR (DMSO-d₆): delta 8-7.3 (m, 3H), 6.7(s, 1H) 4.4 (m, 2H), 3.7 (m, 2H), 3.5 (q, 2H), 2.8 (s, 3H), 1.1 (t, 3H).

2-ethoxyethyl 4-(3-methyl-5-isoxazolyl)-thiazole-2-oxamate, Yield, 91%;m.p. 155°-156° C. (acetonitrile); 1HNMR (DMSO-d₆): delta 8.0 (s, 1H),6.7 (s, 1H), 4.5 (m, 2H), 3.8 (m, 2H), 3.6 (q, 2H), 2.3 (s, 3H), 1.1 (t,3H).

2-ethoxyethyl 4-(3-carbethoxy-5-isoxazolyl)-thiazole-2-oxamate, Yield,75%; m.p. 145°-146° C. (acetonitrile); 1HNMR (CDCl₃): delta 7.7 (s, 1H),7.0 (s, 1H), 4.5 (q, 2H), 4.5 (m, 2H), 3.8 (m, 2H), 3.6 (q, 2H), 1.4 (t,3H), 1.2 (t, 3H).

2-ethoxyethyl 4-(3-methoxymethyl-5-isoxazolyl)-thiazole-2-oxamate,Yield, 86%; m.p. 136°-137° C. (ethyl alcohol); 1HNMR (DMSO-d₆): delta8.1 (s, 1H), 6.8 (s, 1H), 4.6 (s, 2H), 4.4 (m, 2H), 3.7 (m, 2H), 3.6 (q,2H), 3.4 (s, 3H), 1.2 (t, 3H).

2-ethoxyethyl 4-(5-hydroxymethyl-3-isoxazolyl)-thiazole-2-oxamate,Yield, 58%; m.p. 159°-161° C. (acetonitrile); 1HNMR (DMSO-d₆): delta 8.0(s, 1H), 6.9 (s, 1H), 4.7 (s, 2H), 4.5 (m, 2H), 3.8 (m, 2H), 3.6 (q,2H), 1.2 (t, 3H).

2-ethoxyethyl 4-(3-hydroxy-5-isoxazolyl)-thiazole-2-oxmate, m.p.217°-219° C. (acetonitrile); 1HNMR (DMSO-d₆); delta 8.00 (s, 1H), 6.37(s, 1H), 4.43 (m, 2H), 3.73 (m, 2H), 3.53 (q, 2H), 1.13 (t, 3H).

2-ethoxyethyl 4-(3-bromo-5-isoxazolyl)-5-ethyl-thiazole-2-oxamate,Yield, 92%; m.p. 128°-129° C. (acetonitrile); 1HNMR (DMSO-d₆): delta 7.0(s, 1H), 4.4 (m, 2H), 3.7 (m, 2H), 3.5 (q, 2H), 3.1 (q, 2H), 1.3 (t,3H), 1.1 (t, 3H).

ethoxyethyl 4-(3-bromo-5-isoxazolyl)-thiazole-2-oxamate, Yield, 70%;m.p. 162°-164° C. (acetonitrile); 1HNMR (DMSO-d₆): delta 8.2 (s, 1H),7.1 (s, 1H), 4.5 (m, 2H), 3.8 (m, 2H), 3.6 (q, 2H), 1.18 (t, 3H).

2-ethoxyethyl 4-(3-chloro-5-isoxazolyl)-thiazole-2-oxamate, Yield, 81%;m.p. 154°-156° C. (acetonitrile); 1HNMR (DMSO-d₆): delta 8.2 (s, 1H),7.1 (s, 1H), 4.5 (m, 2H), 3.8 (m, 2H), 3.6 (q, 2H), 1.2 (t, 3H).

2-ethoxyethyl 4-(3-methoxy-5-isoxazolyl)-thiazole-2-oxamate, Yield, 78%;m.p. 142°-143° C. (acetonitrile); 1HNMR (DMSO-d₆): delta 8.10 (s, 1H),6.58 (s, 1H), 4.5 (m, 2H), 4.02 (s, 3H), 3.8 (m, 2H), 3.60 (q, 2H), 1.18(t, 3H).

2-ethoxyethyl 4-(3-phenyl-5-methyl-4-isoxazolyl)-thiazole-2-oxamate,Yield, 80%; m.p. 113°-115° C. (ethyl alcohol); 1HNMR (DMSO-d₆): delta7.50 (m, 5H), 7.20 (s, 1H), 4.4 (m, 2H), 3.7 (m, 2H), 3.5 (q, 2H), 2.57(s, 3H), 1.13 (t, 3H).

(4) 2-methoxyethyl 4-(3-bromo-5-isoxazolyl)-thiazole-2-oxamate,

To a mixture of 2.50 g (10 mmol) of2-amino-4-(bromo-5-isoxazolyl)-2-thiazole and 1.16 g (11.5 mmol) oftriethylamine in 20 ml of pyridine stirred continously at a temperatureof 5° C. were added dropwise 1.91 g (11.5 mmole) of2-methoxy-ethyl-oxalyl chloride (prepared by adding 2-methoxy-ethanol toan excess of oxalyl chloride and collecting by distillation of thefraction with b.p. 124°-128° C./90 mmHg). At the end of the addition thesolution was stirred for one night and then diluted with 50 ml of water.

The precipitate was collected by filtration under reduced pressure,washed abundantly on the filter with water, and dried under reducedpressure at 50° C. 3.10 of raw material were obtained which wererecrystallized twice from acetonitrile to give 2.30 g (61%) of ananalytically pure crystalline compound, m.p. 175.5°-177° C.; 1HNMR(DMSO-d₆): delta 8.17 (s, 1H); 7.13 (s, 1H); 4.50 (m, 2H,); 3.50 (m,2H); 3.35 (s, 3H).

EXAMPLE F (1) 4-(3-bromo-5-isoxazolyl)-thiazole-2-oxamic acid

A suspension of 12.60 g (36.4 mmol) of ethyl4-(3-bromo-5-isoxazolyl)-thiazole-2-oxamate in 500 ml of N/10 sodiumhydroxide was stirred at 40° C. for 45 minutes.

The reaction mixture was cooled to room temperature, extracted twicewith 150 ml of ethyl ether, treated with active charcoal, and filtered.

The filtrate was acidified with 60 ml of 1N hydrochloric acid and theprecipitate was collected by filtration and washed on the filterabundantly with water. 9.80 g (84.5%); m.p. 217°-218.5° C. (dec.). 1HNMR(DMSO-d₆): delta 8.13 (s, 1H); 7.16 (s, 1H).

(2) 2-aminoethanol 4-(3-bromo-5-isoxazolyl)-thiazole-2-oxamate salt

A suspension of 2.85 g (8.95 mmol) of4-(3-bromo-5-isoxazolyl)-thiazole-2-oxamic acid in 25 ml of ethanol washeated on a steam-bath while stirring. To this mixture were added 0.59 g(9.66 mmol) of ethanolamine in 10 ml of ethyl alcohol and 20 ml ofwater.

The solution was cooled to room temperature and then allowed to stand at4° C. for one night.

The precipitate was collected by filtration, dried and recrystallizedfrom 65 ml of a 2:1 ethyl alcohol/water mixture. Yield, 2 g (59%); m.p.190°-193° C. (dec.). 1HNMR (DMSO-d₆): 8.0 (s, 1H), 7 (s, 1H), 3.7 (m,2H), 3.0 (m, 2H).

(3) tromethamine 4-(3-bromo-5-isoxazolyl)-thiazole-2-oxamate salt

To a solution of 3.20 g (26.4 mmol) of tromethamine in 75 ml ofmethanol, kept under stirring with slight refluxing, were added all atonce 8.4 g (26.3 mmole) of 4-(3-bromo-5-isoxazolyl-2-thiazolyl oxamicacid.

The reaction mixture was cooled to room temperature and afterapproximately 15 minutes the precipitate was collected by filtration,washed on the filter with cold methanol, and dried.

The crude compound (7.10 g; 61.5%) was recrystallized from methanol;m.p. 183° C. (dec.); 1HNMR (DMSO-d₆ +D₂ O): delta 8.07 (s, 1H); 7.17 (s,1H); 3.65 (s, 6H).

(4) L-lysine 4-(3-bromo-5-isoxazolyl)-thiazole-2-oxamate salt

2.6 g (8.2 mmol) of 4-(3-bromo-5-isoxazolyl)-thiazole-2-oxamic acid wereadded to a solution of 1.25 g (8.6 mmol) of L-lysine in 140 ml of 75%aqueous ethyl alcohol while refluxing and stirring.

After cooling to 0° C. the mixture was maintained under stirring for 3hours. The precipitate was collected by filtration; yield, 2.7 g (71%);m.p. 196°-197° C. (dec.); 1HNMR (D₂ O): delta 7.5 (s, 1H), 6.5 (s, 1H),3.9 (t, 3H), 3.1 (m, 2H), 2.2-1.3 (m, 6H).

In a similar manner were prepared the following compounds:

4-(3-methoxy-5-isoxazolyl)-thiazole-2-oxamic acid, Yield, 82%; m.p.224°-225° C. (dec.); 1HNMR (DMSO-d₆): delta 8.0 (s, 1H), 6.5 (s, 1H),4.0 (s, 3H).

2-aminoethanol 4-(3-methoxy-5-isoxazolyl)-thiazole-2-oxamate salt,Yield, 83.7%; m.p. 214°-215° C. dec. (75% ethyl alcohol); 1HNMR(DMSO-d₆): delta 7.1 (s, 1H), 6.5 (s, 1H), 4.0 (s, 3H), 3.7 (m, 2H), 3.0(m, 2H).

2-aminoethanol 4-(3-chloro-5-isoxazolyl)-thiazole-2-oxamate salt, Yield,71%; m.p. 211° C. dec. (70% ethyl alcohol); 1HNMR (TFAA): delta 8.1 (s,1H), 7.1 (s, 1H), 3.7 (m, 2H), 3.0 (m, 2H).

2-aminoethanol 4-(5-phenyl-3-isoxazolyl)-thiazole-2-oxamate salt, Yield,68.5%; m.p. 210°-211° C. dec. (75% methyl alcohol); 1HNMR (DMSO d₆):delta 8.2-7.1 (m, 5H), 8.2 (s, 1H), 7.4 (s, 1H), 3.8 (m, 2H), 3.0 (m,2H).

2-aminoethanol 4-(3-phenyl-5-isoxazolyl)-thiazole-2-oxamate salt, Yield,73%; m.p. 207°-208° C. dec. (85% ethyl alcohol); 1HNMR (DMSO-d₆): delta9-7.3 (m, 6H), 7.4 (s, 1H), 3.8 (m, 2H), 3.1 (m, 2H).

L-lysine 4-(5-phenyl-3-isoxazolyl)-thiazole-2-oxamate salt, Yield,64.5%; m.p. 240°-241° C. dec. (20% methyl alcohol); 1HNMR (TFAA): delta8.1-7.3 (m, 5H), 8.0 (s, 1H), 7.3 (s, 1H), 4.0 (t, 1H), 2.9 (m, 2H),2.2-1.3 (m, 6H).

2-aminoethanol4-[3-(2-chloro-6-fluorophenyl)-5-isoxazolyl]-thiazole-2-oxamate salt,Yield, 56%; m.p. 230°-231° C., dec. (70% ethyl alcohol); 1HNMR(DMSO-d₆): delta 8.2-7.0 (m, 3H), 8.1 (s, 1H), 7.1 (s, 1H), 3.7 (m, 2H),3.0 (m, 2H).

4-(3-phenyl-5-methyl-4-isoxazolyl)-thiazole-2-oxamic acid, Yield, 62%;m.p. 187°-188° C., dec. (isopropyl alcohol); 1HNMR (DMSO-d₆): delta 7.6(m, 5H), 7.2 (s, 1H), 2.6 (s, 3H).

2-aminoethanol4-[3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolyl]-thiazole-2-oxamatesalts, Yield, 60%; m.p. 164°-166° C., dec. (isopropyl alcohol); 1HNMR(DMSO, d₆): delta 8-7.3 (m, 3H), 6.6 (s, 1H), 3.7 (m, 2H), 2.9 (m, 2H),2.8 (s, 3H).

2-aminoethanol 4-(5-hydroxymethyl-3-isoxazolyl)-thiazole-2-oxamatesalts, Yield, 61%; m.p. 185°-187° C., dec. (methyl alcohol); 1HNMR(DMSO-d₆): delta 7.9 (s, 1H), 6.8 (s, 1H), 4.6 (s, 2H), 3.7 (m, 2H), 3.0(m, 2H).

2-aminoethanol 4-(3-hydroxymethyl-5-isoxazolyl)-thiazole-2-oxamatesalts, Yield, 69%; m.p. 196°-197° C., dec. (75% methyl alcohol); 1HNMR(DMSO-d₆): delta 7.9 (s, 1H), 6.8 (s, 1H), 4.6 (s, 2H), 3.7 (m, 2H), 3.0(m, 2H).

(5) Sodium 4-(3-methoxy-5-isoxazolyl)-thiazole-2-oxamate salts

A suspension of 11.9 g (35 mmol) of ethoxyethyl4-(3-metoxy-5-isoxazolyl)-thiazole-2-oxamate in 500 ml of N/10 sodiumhydroxide was stirred at 40° C. for 30 minutes.

After cooling to 0° C., the precipitate was collected by filtration anddried. Yield, 2.4 g (23.5%); m.p. 320° C., dec. 1HNMR (TFAA): delta 8.1(s, 1H), 6.8 (s, 1H), 4.2 (s, 3H).

EXAMPLE G (1) N-[4-(3-bromo-5-isoxazolyl)-2-thiazolyl]-oxamide

A mixture of 3.50 g (10 mmol) of ethyl4-(3-bromo-5-isoxazolyl)-thiazole-2-oxamate and 25 ml of a 10% solutionof ammonia in methyl alcohol was stirred at room temperature for 24hours.

The precipitate was collected by filtration, dried under reducedpressure at 50° C. (2.70 g) and recrystallized from 55 ml of glacialacetic acid to give 2.20 g (69%) of analytically pure crystallineproduct which decomposes without melting at 255° C. 1HNMR (DMSO-d₆):delta 8.20 (s, 1H), 7.20 (s, 1H)

(2) N-[4-(3-methoxy-5-isoxazolyl)-2-thiazolyl]-oxamide

A mixture of 8.6 g (28.9 mmol) of ethyl4-(3-methoxy-5-isoxazolyl)-thiazole-2-oxamate in 143 ml of a 16%ammonium hydroxide solution in methyl alcohol was stirred overnight atroom temperature.

The solvent was evaporated and the residue (7.5 g) was recrystallizedfrom 220 ml of glacial acetic acid. Yield, 6.2 g (80%); crystallinecompound which decomposes at 250° C. without melting. 1HNMR (DMSO-d₆):delta 8.0 (s, 1H), 6.5 (s, 1H), 4.0 (s, 3H).

In a similar manner were prepared the following compounds:

N-[4-(3-phenyl-5-methyl-4-isoxazolyl)-2-thiazolyl]-oxamide, Yield, 73%;m.p. 204°-205° C. (acetonitrile); 1HNMR (DMSO-d₆): delta 7.6 (m, 5H),7.2 (s, 1H), 2.6 (s, 3H).

N-[4-(5-phenyl-3-isoxazolyl)-2-thiazolyl]-oxamide, Yield, 74%; m.p.246°-247° C. (glacial acetic acid); 1HNMR (DMSO-d₆): delta 8.2-7.4 (m,5H), 8.1 (s, H), 7.5 (s, 1H).

N-[(4-(2-chloro-6-fluorophenyl)-5-isoxazolyl)-2-thiazolyl]-oxamide,Yield, 77%, m.p. 235°-237° C. (glacial acetic acid); 1HNMR (DMSO-d₆):delta 8.2 (s, 1H), 7.6 (m, 3H), 7.2 (s, 1H).

N[4-(3-methyl-5-isoxazolyl)-2-thiazolyl]-oxamide, Yield, 90%; m.p.245°-246° C. (glacial acetic acid); 1HNMR (DMSO-d₆): delta 8.0 (s, 1H),6.7 (s, 1H), 3.3 (s, 3H).

N-[4-(3-bromo-5-isoxazolyl)-5-ethyl-2-thiazolyl]-oxamide, Yield, 85%;210°-221° C., dec. (glacial acetic acid); 1HNMR (DMSO-d₆): delta 7.0 (s,1H), 3.1 (q, 2H), 1.3 (t, 3H).

N-[4-(3-hydroxymethyl-5-isoxazolyl)-2-thiazolyl]-oxamide, Yield, 45%,250°-255° C., dec. (glacial acetic acid); 1HNMR (DMSO-d₆): delta 8.0 (s,1H), 6.8 (s, 1H), 4.6 (s, 2H).

(3) 1-[4-(3-bromo-5-isoxazolyl)-thiazole-2-oxamoyl]-4-methyl-pyperazine

A mixture of 7.3 g (21.1 mmol) of ethyl4-(3-bromo-5-isoxazolyl)-thiazole-2-oxamate and 36.5 ml ofN-methyl-pyperazine was stirred overnight at room temperature.

The solution was then poured into 350 ml of isopropyl ether whilestirring, the precipitate was collected by filtration and taken up withhot methyl alcohol.

The suspension was refluxed and stirred for 30 minutes, and then cooledto 0° C. and filtered.

The residual of the filtration was dissolved at 100° C. in 80 ml ofdimethylformamide. The solution was cooled to 0° C., the precipitate wascollected by filtration and dried. Yield, 3.5 g (41.5%) of a crystallinecompound which melts slowly at 200° C.; 1HNMR (TFAA): delta 8.1 (s, 1H),7.2 (s, 1H), 4.2-3.2 (m, 8H), 3.2 (s, 3H).

(4) N,N'-bis-[4-(3-bromo-5-isoxazolyl)-2-thiazolyl]-oxamide

To a solution of 10.1 g (41 mmol) of2-amino-4-(3-bromo-5-isoxazolyl)-thiazole in 160 ml of1,2-dichloroethane were added 4.13 g (41 mmol) of triethylamine in 15 mlof 1,2-dichloroethane.

The mixture was heated to 60° C. and stirred; a solution of 2.60 (20.5mmol) of oxalyl chloride in 15 ml of 1,2-dichloromethane was addedslowly dropwise.

The thus obtained mixture was stirred overnight at room temperature. Theprecipitate was collected by filtration and washed with methyl alcohol.

The crude product (5.8 g) was recrystallized from 195 ml oftetrahydrofuran. Yield, 4.5 g (40%) of a crystalline compound whichdecomposes slowly at 280° C. 1HNMR (DMSO-d₆): delta 8.1 (s, 1H), 7.1 (s,1H).

(5) N-[4-(3-bromo-5-isoxazolyl)-2-thiazolyl]-N'-isopropyl-oxamide

A solution of 7.1 g (20.5 mmol) of ethyl4-(3-bromo-5-isoxazolyl)-thiazole-2-oxamate in 30 ml of isopropylaminewas stirred overnight at room temperature.

The solvent was removed by evaporation and the residue was crystallizedfrom 300 ml of methyl alcohol. Yield, 3.2 g (43.5%); m.p. 194°-195° C.;1HNMR (DMSO-d₆): delta 8.1 (s, 1H), 7.1 (s, 1H), 7.1 (s, 1H), 4.1 (m,1H), 1.2 (d, 6H).

What is claimed:
 1. A compound of formula: ##STR8## wherein R and R₁which may be the same or different represent a hydroxy group; a hydrogenor halogen atom; a C₁ -C₆ alkyl or alkoxy group optionally substitutedby from one to three substituents selected from the group consisting ofhalogen, hydroxy, alkoxy, amino, carboxy, alkoxycarbonyl, alkoxalyloxy,and phenyl, the latter in turn optionally substituted by from one tothree substituents selected from the group consisting of halogen,hydroxy, alkoxy, amino and trifluoroalkyl; a phenyl group optionallysubstituted by from one to three substituents selected from the groupconsisting of halogen, hydroxy, alkoxy, amino and trifluoromethyl;R₂ isa hydroxy group, an OR₃ group or an NR₄ R₅ group; R₃ is a C₁ -C₆ alkylgroup optionally substituted with from one to three substituentsselected from the group consisting of hydroxy, alkoxy, amino, carboxyand alkoxycarbonyl; a C₅₋₆ cycloalkyl group optionally substituted byfrom one to three alkyl groups; a C₇ -C₉ phenylalkyl group optionallysubstituted on the phenyl ring by from one to three substituentsselected from the group consisting of halogen, methyl and methoxy group;a group of the formula --(CH₂ --CH₂ --O)_(n) --R₆ wherein n is aninteger number of 2 to 4 and R₆ is a hydrogen atom or an alkyl group; R₄and R₅ which may be the same or different are a hydrogen atom, an alkyl,a C₅ -C₆ cycloalkyl, a C₇ -C₉ phenylalkyl or a phenyl group; or R₄ andR₅ together with the nitrogen atom to which they are linked, form a1-piperidyl, 1-piperazinyl, 4-methyl-1-piperazinyl, pirazolyl thiazolylor imidazolyl radical; or either R₄ or R₅ is a hydrogen atom and theother a group of the formula ##STR9## wherein R and R₁ have the aboveindicated meanings; R₇ is a hydrogen atom or a C₁ -C₃ alkyl radical; andpharmaceutically acceptable salts thereof with organic and inorganicbases when R₂ is a hydroxy group and with organic and inorganic acidswhen R₂ contains a basic function; with the proviso that R₂ is not ahydroxy group or an OR₃ group when the isoxazolyl radical is a 3- or a5-isoxazolyl radical.
 2. A compound according to claim 1, wherein R andR₁ are each independently hydrogen, chlorine, bromine, hydroxy, methyl,methoxy, ethoxy, benzyloxy, phenyl, halosubstituted phenyl,hydroxymethyl, methoxymethyl, ethoxymethyl or carbethoxy; R₂ is ahydroxy group, an OR₃ or NR₄ R₅ group where in turn R₃ is ethoxyethyl,ethyl, cyclohexyl or phenylmethyl; R₄ and R₅ are each independentlyhydrogen, C₁₋₄ alkyl or a bromo-isoxazolyl-thiazole group; R₄ and R₅together with the nitrogen atom to which they are linked form a4-methyl-pyperazinyl group. 3.N-[4-(3-bromo-5-isoxazolyl)-2-thiazolyl]-oxamide. 4.N,N'-[4-(3-bromo-5-isoxazolyl)-2-thiazolyl]-oxamide.
 5. A pharmaceuticalcomposition having antiarthritic activity and containing an effectiveamount for the purpose of a compound according to claims 1 or 2 or 3 or4.
 6. Method of treating a subject having symptoms of arthritiscomprising administering to such subject a pharmaceutical compositionhaving antiarthritic activity wherein the active ingredient is present,in an effective amount for the purpose, of a compound according to claim1 or 2 or 3 or
 4. 7. A compound of formula ##STR10## wherein R and R₁are each independently hydrogen, chlorine, bromine, hydroxy, methyl,methoxy, ethoxy, benzyloxy, phenyl, halo substituted phenyl,hydroxymethyl, methoxymethyl, ethoxymethyl or carbethoxy; andR₇ ishydrogen or C₁₋₃ alkyl.